1. Field of the Invention
The present invention relates to the combination of one or more CB1 receptor antagonists and of one or more products which activate dopaminergic neurotransmission in the brain, to the pharmaceutical compositions comprising them and to their use in the treatment of Parkinson's disease.
2. Description of the Art
CB1 receptor antagonists have been developed for the treatment of schizophrenia (D. Kendall, Curr. Opin. Cent. Peripher. Nerv. Syst. Invest. Drugs, 2(1), 112–122, 2000), for their effect on food intake (G. Colombo et al., Life Sciences, 63 (8), 113–117 (1998); J. Siamand et al., Behavioral Pharmacol., 9, 179–181 (1998)) and for the treatment of Parkinson's disease, epilepsy, migraine and stress (G. Gerdeman, D M. Lovinger, J. Neurophysiol., 85(1), 468–471, 2001; WO 0046209).
Parkinson's disease results from a chronic and progressive neurological disorder. It is based on a deficiency of dopamine and a relative excess of acetylcholine and is associated with destruction of the dopaminergic neurons which participate in the control of the motor activities (H. Lullmann et al., Atlas de poche de pharmacologie [Pocket atlas of pharmacology], 2nd Ed., Medecine-Sciences, Flammarion, ISBN2-257-12119-8). The treatment of Parkinson's disease is mainly pharmacological and involves various medicaments intended to increase the amount of dopamine present in the brain.
As dopamine does not pass through the hematoencephalic barrier, levodopa, a precursor of dopamine converted to dopamine by dopa decarboxylase, was developed in the 1960s. Levodopa remains today the first treatment of choice for Parkinson's disease and initially gives good results. However, after several years, fluctuations in response (on-off effect), a decrease in its effectiveness as the disease progresses (wearing-off effect) and in particular dyskinesias (involuntary abnormal movements) are observed in the majority of patients. A psychotic state may also be observed.
Other medicaments, such as dopaminergic agonists, are also recommended, alone or in combination with levodopa, and have as main aim that of reducing, at least, the undesirable effects of the latter. For some years, selective inhibitors of monoamine oxidase MAO-B, an enzyme which decomposes dopamine in the brain, and inhibitors of catechol-O-methyltransferase (COMT), an enzyme which prevents levodopa from crossing the hematoencephalic barrier, have been developed and prescribed in combination with levodopa. Significant side effects have also been observed with these therapies.
All of the references described herein are incorporated herein by reference in their entirety.